Project Summary While decline in lung function occurs in all people as part of aging, it is accelerated in susceptible cigarette smokers, leading to increased risk for chronic obstructive pulmonary disease (COPD) and premature death. A key risk factor that plays an important role for accelerated loss of lung function is genetic variation that predisposes people to rapidly lose lung function. Based on our studies showing the importance of Bik in lung epithelial cell death, we investigated genetic variants for the BIK gene and identified a single nucleotide polymorphism (SNP) in the first intron (rs738276) that is associated with greater decline in lung function in three different cohorts; the Lovelace Smokers Cohort (LSC), the Normative Aging Study (NAS), and the ECLIPSE cohort. Because the G allele in this SNP reduces BIK promoter activity and causes reduced Bik expression in airway and lymphoblastoid cells, we examined whether a lung pathology occurs in Bik-deficient mice. We found that the lung morphology is similar in bik+/+ and bik-/- mice up to the age of 65 weeks but that bik-/- mice express higher Bak levels and develop extensive emphysema after 65-80 weeks of age compared with bik+/+ mice. The parent grant is focused on the molecular interaction of Bik with other proteins to induce cell death and to develop effective Bik-derived peptides that can be used to reduce allergen-induced mucous cell metaplasia. The objective of this Revised Application is to test the following central hypotheses: In Bik- deficient mice, Bak causes death of senescent alveolar epithelial cells to cause emphysema in aging mice. Further, subjects over 60 years of age with the GG compared to the AA genotype for SNP rs738276 show increased Bak expression in the alveolar epithelial cells and emphysema on computed tomography (CT). In Aim 1, we will determine whether the development of COPD in aging bik-/- mice is due to the compensatory increase in Bak levels. We will generate bik-/-/bak-/- double knockout mice and age these mice along with bik-/- and bak-/- mice up to 80 weeks of age and analyze the lung pathology for emphysematous changes. We will also breed CCSP promoter inducible Bik transgene into the bik-/- mice to evaluate whether Bik expression in the airway cells will reverse the development of emphysema. In Aim 2, we will evaluate expression of Bak protein levels in alveolar epithelial cells from 50 subjects with GG and AA alleles (BIK SNP rs738276), who will be matched for age, sex, and smoking. We will also compare emphysema in these subjects with GG and AA alleles from computed tomography scans. Lung tissue samples will be provided by the National Lung Research Consortium (LTRC). The proposed research will establish a novel role for Bik in COPD pathogenesis by affecting apoptosis processes differentially in bronchial and alveolar epithelial cells. In the future, restoring norma Bik expression may lead to novel preventive and/or treatment strategies for COPD.